Rapid Antidepressant Properties Research Articles

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats.

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

[Ketamine in antidepressant treatment: a revolution?]

Thirty percent of depressed patients are treatment resistant (TRD) suggesting the need of new therapeutic strategy. Recently, it has been shown that ketamine, an anesthetic agent with dissociative effects, has potent and rapid antidepressant properties. Ketamine is a ionotropic glutamatergic NMDA antagonist that inhibits gabaergic neurons. Its antidepressant effect peaks at 24 h post-treatment. Several meta-analyses of placebo randomized clinical trials emphasized its efficacy. More recently, a meta-analysis showed its efficiency in real-world population of TRD patients. Although there is no clear biological or clinical predictors of response or remission to ketamine, patients with high level of resistance were found to remit less often. Restoring both the optimism bias and the asymmetry in belief updating mediates the antidepressant ketamine's effect. Consistent with predictive bayesian model and terror management theory, this suggests that dissociation induced by ketamine may contribute to its clinical antidepressant action. Although increasing access to ketamine and esketamine is welcome, legitimate concerns have been raised with respect to long-term safety and abuse risk.

A Brief, Fully Automated Neurocognitive Training Intervention Extends the Antidepressant Effect of a Single Ketamine Infusion

Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. We posited that ketamine would provide a clinical window of opportunity in which to introduce automated neurocognitive training techniques to consolidate adaptive forms of cognitive processing (specifically, positive implicit representations of self) while neuroplasticity remains high.

Ketamine’s Rapid Antidepressant Action is Associated With Changes in the Functional Connectivity of the Habenula

Ketamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure which modulates reward and affective states.

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers.

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine’s effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

Microglial activation and psychiatric diseases

In recent decades, comprehensive evidence has accumulated that inflammation and microglia activation might be implied in the etiology of psychiatric disorders. The study of the activation state of microglia is based on the histological study of brains of deceased patients suffering from psychiatric disorders, leading to partial and biased data. The understanding of the role of microglia is yet crucial in order to develop innovative treatments. For example, ketamine has recently shown rapid antidepressant properties related to its activity of NDMA antagonism and its immunomodulatory properties. In our work, we used a translational approach to find biomarkers of the activation state of microglia in psychiatric patients that can be determined during patient care. First, in a murine model of LPS-induced depressive-like behavior, we observed that ketamine injection reversed the morphological microglial alterations and reduced microglial activation markers, such as quinolinic acid (QUIN) level in brain. Second, in 15 patients with treatment-resistant depressive episode, treated by a cycle of ketamine infusions (0.5 mg/kg iv), we showed that the initial ratio of kynurenic acid (KYNA) to QUIN is a predictor of the antidepressant response (measured with the MADRS score) after ketamine infusion and at the end of the cycle (beta = 0.28 ± 0.07, P = 0.0002 and beta = 1.05 ± 0.35, P = 0.016 respectively). The variation in QUIN concentration after ketamine infusion is also a predictor of the change in MADRS score following this infusion (beta = 0.35 ± 0.14, P = 0.015). High concentrations of QUIN may then be a predictor of ketamine efficacy in patients with treatment-resistant depression and define a sub-group of patients who may have microglial alterations. This imbalance in kynurenine pathway may also be explored in other psychiatric disorders with inflammatory component and in patients with rare inflammatory diseases associated with psychiatric symptoms.

Experts Remain Enthusiastic About NMDA-Targeting Antidepressants

Back to table of contents Previous article Next article PsychopharmacologyFull AccessExperts Remain Enthusiastic About NMDA-Targeting AntidepressantsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:2 Mar 2018https://doi.org/10.1176/appi.pn.2018.pp3a3AbstractThough several promising investigational compounds that regulate glutamate signaling have faltered in recent clinical studies, upcoming data on esketamine and rapastinel may turn the tide.When the anesthetic ketamine was first shown to have strong and rapid antidepressant properties back in 2000, it triggered a wave of excitement in the psychiatric community. Studies of mood disorders have long focused on serotonin and dopamine signaling in the brain, but ketamine blocks the NMDA receptor and affects glutamate signaling. Though ketamine has properties that limit its therapeutic potential (it needs to be given intravenously or intranasally for several minutes and induces dissociative anesthesia that can lead to delirium and increase likelihood for abuse), the demonstrated effectiveness of the agent opened the floodgates to new areas of antidepressant research and drug development.Over the past few years, the waters have appeared to recede. Many existing or newly developed compounds have shown some initial promise only to underperform in larger human studies of depression. Roche’s experimental drug basimglurant failed to improve depressive symptom scores when given as an adjunct in a phase 2 study completed in 2016. AstraZeneca’s lanicemine, which appeared promising in a short-term phase 2 study in 2014, faltered in a replication study, showing no difference over placebo following 12 weeks of treatment.Gerard Sanacora, M.D., Ph.D., says drugs that aim to act exclusively on NMDA receptors may have fewer side effects than ketamine but may also suffer from decreased potency. Despite being one of the lead investigators on the replication study of lanicemine, Gerard Sanacora, M.D., Ph.D., a professor of psychiatry at Yale University School of Medicine and director of Yale’s Depression Research Program remains bullish on NMDA receptors as antidepressant targets.He said that part of the difficulty in trying to recreate ketamine’s effects is that ketamine is what he calls a “dirty drug.” Ketamine interacts with multiple targets beyond NMDA receptors, and likely alters glutamate activity through both direct and indirect mechanisms. Other drugs that aim to act exclusively on NMDA receptors may have fewer side effects than ketamine but may also suffer from decreased potency. “I also think an important facet of drug development that gets overlooked in the media is that there are a lot of factors that go into R&D decisions,” Sanacora told Psychiatric News. “Whenever a drug falls off the clinical pipeline, it’s interpreted that the drug doesn’t work, but that is not always the case.”Sanacora pointed to the decision to abandon traxoprodil—an NMDA-blocking compound that was developed at Pfizer—as an example of the challenges companies face when deciding whether to move forward with development of a drug that shows promise. In 2006, Pfizer conducted a 30-person clinical study testing traxoprodil for treatment-resistant depression. The study found that 60 percent of the patients receiving traxoprodil responded to the medication compared with only 20 percent of the placebo group. Because of concerns that patients taking the medication might experience cardiac problems from QTc prolongation as well as the short patent life of the drug, the company decided not to pursue an antidepressant indication.In the case of lanicemine, Sanacora noted that in both phase 2 clinical studies the medication showed a robust antidepressant effect; however, in the replication study, patients in the placebo group also experienced a very large, 13.2-point decrease on the MADRS (Montgomery-Asberg Depression Rating Scale) at the six-week primary end point. While patients in the lanicemine group experienced a drop in MADRS of 14.4, the medication did not show superiority to placebo.“The trial results were discouraging, but this lack of success is not unique to any class of drugs,” Sanacora said. “It’s really hard to conduct clinical trials in depression.”Sanjay Mathew, M.D., thinks that esketamine is a key drug to watch in 2018; if approved by the FDA, esketamine would be only the second psychotropic that would have an FDA indication to reduce the risk of suicide.Sanjay Mathew, M.D., the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Chair for Research in Psychiatry at Baylor College of Medicine agreed with Sanacora’s assessment. “Depression is an extremely heterogeneous condition, and without biomarkers, which can be used in clinical trials for diagnostic and prognostic purposes, we are severely handicapped in our ability to identify those patients who might benefit from specific drugs,” he said. Despite setbacks, Sanacora and Mathew said there is reason to be hopeful about NMDA drug development. Mathew said esketamine—the purified, left-handed version of the ketamine molecule (regular ketamine solutions contain both left- and right-handed molecules)—is particularly worth tracking in the coming year. A phase 3 study of intranasal esketamine sponsored by Johnson & Johnson recently wrapped up and the results from the trial are expected soon.“The drug has received FDA [Food and Drug Administration] ‘fast track’ status for acute suicidal ideation and behavior, so that would be a first, if successful, to have an antidepressant medication FDA approved for the treatment of suicidality,” Mathew said. “That would be a very big deal, as the only drug we have in psychiatry with a FDA suicide indication is clozapine, for the treatment of suicidality in schizophrenia and schizoaffective disorder.”Sanacora added that a few other investigational NMDA-receptor modulators such as rapastinel are also being tested in large clinical studies that should be completed in the coming year. Even if these drugs aren’t proven to be effective antidepressants, he said he believes the results will provide important information about glutamate-targeting drugs. “I've done a lot of prognosticating over the years based on relatively limited data,” Sanacora said, “but soon I, along with others, will have much more quality data to consider.” ■Back to Psychopharmacology Newsletter Table of Contents ISSUES NewArchived

Ketamine and Sleep: Bridging the Gap in the Treatment of Depressive Illness

Two articles that provide the first clear evidence for a connection between the rapid antidepressant effects of ketamine and sleep appear in this issue of Biological Psychiatry ( 1 Duncan Jr, W.C. Slonena E. Hejazi N.S. Brutsche N. Yu K.C. Park L. et al. Motor-activity markers of circadian timekeeping are related to ketamine’s rapid antidepressant properties. Biol Psychiatry. 2017; 82: 361-369 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 2 Orozco-Solis R. Montellier E. Aguilar-Amal L. Sato S. Vawter M.P. Bunney B.G. et al. A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex. Biol Psychiatry. 2017; 82: 351-360 Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar ). These articles are timely considering the explosion of interest in providing ketamine treatment for depression, and for the fast-growing knowledge base connecting circadian rhythm to depression and other psychiatric illnesses. These articles are also important because of their relation to a fundamental problem in the understanding and treatment of depressive illness more generally. This problem (which continues despite billions spent on the development of new pharmacotherapies) is the long delay between initiation of treatment and significant improvement in the illness. This apparent requirement for an incubation of treatment before achieving meaningful benefit distinguishes psychiatric disorders in general, and depressive disorders in particular, from diseases that are not brain related. A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate CortexBiological PsychiatryVol. 82Issue 5PreviewConventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. Full-Text PDF Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant PropertiesBiological PsychiatryVol. 82Issue 5PreviewThe rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock–associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. Full-Text PDF

A novel triple reuptake inhibitor with rapid antidepressant properties identified by virtual screening (1144.1)

A continuing challenge in treating depression is therapeutic delay and resistance to available treatments. Hence, the growing interest in developing antidepressants (AD) with rapid onset (hours to days) and novel mechanisms of action. For example, the glutamatergic antagonist ketamine has rapid AD efficacy but is limited by poor bioavailability, short duration of effect, and potential for abuse. Here we report MI‐4, identified through virtual screening targeting the human dopamine transporter, inhibited the human monoamine transporters of dopamine (DA), norepinephrine (NE), and serotonin (5‐HT) in vitro. In vivo administration of MI‐4 in mice induced robust, dose‐dependent AD‐like behaviors in acute models of learned helplessness (tail suspension test and forced swim test). Moreover, 21‐day administration of MI‐4 reduced drinking latency times comparable to fluoxetine in the novelty‐induced hypophagia test, which requires chronic treatment to produce AD effects. Interestingly, like ketamine, MI‐4 also exhibits NMDA receptor antagonism and produced rapid (3‐day) and chronic (21‐day) AD‐like effects in the social avoidance test following 10 days of social defeat, by increasing social interaction scores 2‐fold vs. vehicle controls while improving resiliency to near 70%. Unlike ketamine, MI‐4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and DA in vivo microdialysis). These data suggest MI‐4 is a novel, multiple mechanism antidepressant with rapid and chronic properties.

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression.

Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.

Possible mechanism of the antidepressant effect of 3,6′-disinapoyl sucrose fromPolygala tenuifoliaWilld

The present study was designed to observe the effects of 3,6'-disinapoyl sucrose (DISS), an active oligosaccharide ester component obtained from the roots of Polygala tenuifolia Willd., on behavioral and biochemical aspects of depression induced by chronic mild stress (CMS) in rats. It is the first exploration of the possible association between DISS's antidepressant-like effects and biochemical markers of depression, and involved measuring monoamine oxidase (MAO) activity, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. Rats were exposed to stressor once daily for consecutive 5 weeks. DISS and a positive control drug, fluoxetine, were administered via gastric intubation to once daily for consecutive 3 weeks from the third week. The results showed that rats subjected to CMS exhibit a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activity, plasma cortisol levels, and MDA levels were increased, while SOD activity was decreased following CMS exposures. DISS significantly inhibited MAO-A and MAO-B activity and blocked plasma elevated cortisol level, an indicator of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, DISS increases SOD activity, inhibits lipid peroxidation, and lessens production of MDA. These results suggest that DISS may possess potent and rapid antidepressant properties, which are mediated via MAO, the HPA axis and oxidative systems. These antidepressant actions make DISS a potentially valuable drug for the treatment of depression.

Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the chronic mild stress model of depression in mice

Depression is related to alterations of the monoamine oxidase (MAO), hypothalamic-pituitary-adrenal (HPA) axis, and oxidative systems, and some antidepressants achieve their therapeutic effects through alteration of following biochemical markers of depression: MAO-A and MAO-B activities, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. The seeds of Psoralea corylifolia, otherwise known as Buguzhi, have long been used for treatments of various symptoms associated with aging in China. Furocoumarins are the most widespread secondary metabolites in this species. The present study was designed to evaluate the potential antidepressant-like activity of total furocoumarins of P. corylifolia (TFPC) in the chronic mild stress (CMS) model of depression. Mice subjected to CMS exhibited a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activities, plasma cortisol levels, and liver SOD activity and MDA levels were increased following CMS exposures. The time-course for reversal of CMS-induced deficits in sucrose consumption by TFPC was dose-dependent. Thus, the statistically significant effect of the higher dose of TFPC (50 mg/kg body wt.) was observed after 3 days of treatment, while 6 days of treatment were required in the group receiving a lower dose (30 mg/kg body wt.) of TFPC. TFPC reversed these biochemical changes. These results suggest that TFPC may possess potent and rapid antidepressant properties that are mediated via MAO, the HPA axis and oxidative systems and these antidepressant actions could make TFPC a potentially valuable drug for the treatment of depression in the elderly.

Glutamate modulators as novel interventions for mood disorders

Recent evidence suggests that critical molecules in neurotrophic signaling cascades are long-term targets for currently available monoaminergic antidepressants. As chronic and severe mood disorders are characterized by impairments in neuronal resilience, pharmacological strategies that subserve a neuroprotective function might alter disorder pathophysiology and modify disease progression. Several promising approaches involve modulation of the glutamate neurotransmitter system, via post-synaptic receptor blockade or potentiation and presynaptic vesicular release inhibition. A focused review of the extant scientific literature was conducted, with a discussion of 3 compounds or classes of drugs currently undergoing clinical investigation: ketamine, riluzole, and AMPA receptor potentiators. Recent investigations in mood disordered patients suggest that the NMDA receptor antagonist ketamine might demonstrate rapid antidepressant properties. Riluzole has been shown to reverse glutamate-mediated impairments in neuronal plasticity and to stimulate the synthesis of brain derived neurotrophic factor. Open-label trials in treatment-resistant depression have yielded promising results. Likewise, AMPA receptor potentiators favorably impact neurotrophic factors as well as enhance cognition. Pharmacological approaches that modulate components of the glutamate system offer novel targets for severe, recurrent mood disorders. Controlled studies are necessary.

Antidepressant-like action of 5-HT 1A agonists and conventional antidepressants in an animal model of depression

Previous results have suggested that behavioural adaptation to restraint might be promoted by post-restraint stimulation of 5-HT 1A receptors. Therefore, rats were restrained for 2 h and injected with vehicle or 60–1000 μg/kg of the 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) s.c. Vehicle-treated restrained rats showed reduced locomotor activity and increased defaecation in an open field test the day after the end of restraint. A single injection of 250 or 1 000 μg/kg 8-OH-DPAT attenuated these effects. The above locomotor deficits were also attenuated by chronic pretreatment with the antidepressants desipramine and sertraline but not by a single treatment with desipramine or the benzodiazepine anxiolytic drugs chlordiazepoxide and diazepam; none of these treatments unambiguously reversed stress-induced increases in defaecation. Evidence suggests that the above action of 8-OH-DPAT is mediated by 5-HT 1A receptors since it was antagonised by the 5-HT 1A antagonist spiperone but not by the 5-HT 2 antagonist ketanserin and was not mimicked by the 5-HT 1B agonist RU 24969. However, the 5-HT 1A agonists buspirone and TVXQ 7821 (ipsapirone) and the non-specific 5-HT agonist quipazine all possess similar properties to 8-OH-DPAT in this test. The results suggest that 5-HT 1A agonists may have rapid antidepressant properties.